PROJECT SUMMARY The World Health Organization identifies intrauterine growth restriction (IUGR) as a primary risk factor for adverse perinatal outcomes and long-term health consequences. It afflicts an estimated 100,000 children born each year in the United States, with even higher prevalence in developing countries and socioeconomic groups with limited access to healthcare. IUGR is commonly associated with poor maternal nutrition and placental insufficiencies, including immune dysfunction and impaired vascular growth, but how environmental factors regulate these processes is not completely understood. The gut microbiome mediates environmental contributions to host immune function and angiogenesis, and microbiota composition is markedly influenced by dietary intake. This warrants investigation of the microbiome as a critical regulator of placental homeostasis, opening the possibility for microbiota-based therapeutic strategies to treat IUGR. Indeed, this novel approach to improve maternal health during gestation and treat IUGR aligns with the NICHD mission, specifically to ensure ??that women suffer no harmful effects from reproductive processes, and that all children have the chance to achieve their full potential for healthy and productive lives.? My preliminary data supports the central hypothesis that dysbiosis of the maternal microbiome during pregnancy impairs placental angiogenic immune cells and vasculature, leading to downstream abnormalities in fetal development. Further, my data supports the presumption that the microbiome regulates circulating metabolites that have known immunoregulatory and angiogenic potential that can act systemically throughout the host. My rationale is that disrupting the maternal microbiome, whether through bacterial depletion or through maternal nutrition, alters bioavailability of circulating biochemicals that are critical for maternal and fetal health during pregnancy. I propose to test my central hypothesis with the following aims: Aim 1: Investigate effects of the maternal microbiome on placental immune homeostasis; Aim 2: Examine how the maternal microbiome regulates placental vascular development; Aim 3: Determine mechanistic influences of the maternal microbiome on fetal growth. Upon completion, I will provide novel insights into how the maternal microbiome regulates placental immune and vascular homeostasis through specific molecular interactions. This mechanistic approach is significant because it sheds light on a causal role of the microbiome as a regulator of IUGR, and opens the potential for microbiome-based therapeutic targets to markedly improve maternal and fetal health on a global scale. The proposed research is of critical importance for my predoctoral training, as I will develop and refine my technical skills, experimental design and analysis, and critical review of scientific literature from multiple fields.